The present invention relates to a compound that inhibits the binding between Grb2(Growth factor receptor-binding protein-2) and Shc(Src homology and collagen protein) with a consequential effect of suppressing cancer cell proliferation or differentiation; to a process for isolating said compound from Penicillium multicolor F1753; and to a pharmaceutical composition containing same.
Extensive molecular-biochemical studies on normal and transformed cells have revealed that abnormality in the signal transmission involved in the growth and division of cells causes cancer, and also that proteins produced by the expression of oncogenic genes regulate the growth and division of cells. Namely, it has been reported that growth factors, growth factor receptors, intracellular tyrosine phosphorylase""s, Ras proteins, adaptor proteins, transcription factors and the like take part in the intracellular signal transmission and play crucial roles in cell proliferation (see Alexander, L. Eur. J. Biochem. 226, 1-13, 1994).
A series of intracellular signal transmission steps involving Ras protein occur as follows. A signal transmitting substance binds to a growth factor receptor, which causes phosphorylation of tyrosine on the receptors The phosphotyrosine of the activated receptor is recognized by Shc(Src homology and collagen protein), one of adaptor proteins containing SH2 domains, and then, Shc binds to Grb2(Growth factor receptor-binding protein-2) which contains an SH2 domain in the center and SH3 domains at both ends. Grb2 serves to couple the tyrosine-phosphorylated receptor to an important downstream signaling protein Ras, and finally the Ras protein relays the signals delivered intracellularly by such receptors into the cell interior to stimulate cell proliferation and differentiation.
As mentioned above, it is believed that various factors are involved in the intracellular signal transmission and when such signal transmission fails due to disorders in one or more signal transmitting factors, the cell growth becomes abnormal to cause various diseases including cancer.
The present inventors have carried out extensive studies to identify a compound which is capable of intercepting abnormal signal transmission, and have discovered that specific compounds isolated from Penicillium multicolor F1753 exhibit a high inhibitory activity against the binding between Grb2 and Shc.
Accordingly, it is an object of the present invention to provide a novel compound which has a high inhibitory activity against the binding between Grb2 and Shc.
It is another object of the present invention to provide a process for isolating and purifying said compounds from Penicillium microorganisms.
It is a further object of the present invention to provide a pharmaceutical composition containing an effective amount of said compounds.
In accordance with one aspect of the present invention, there is provided a novel compound of formula(I) for inhibiting the binding between Grb2and Shc: 